The spectrum of autoinflammatory diseases: recent bench to bedside observations

Abstract

Purpose of review-The autoinflammatory diseases are a group of conditions that include the hereditary fever syndromes, and result from upregulated innate immune responses. The discovery of the genetic basis for these conditions led to the description of novel intracellular receptors for infectious and noninfectious danger signals. This article focuses on recent progress in our understanding of autoinflammatory syndromes, and how insights into these conditions have triggered the exploration of the role of innate immunity in common rheumatologic diseases.Recent findings-New models for the pathogenesis of several autoinflammatory syndromes have been proposed, including the role of pyrin and cryopyrin in regulating inflammation. Robust evidence has emerged that IL-1β oversecretion is pivotal in cryopyrin-associated periodic syndromes, and that IL-1 inhibition ameliorates the clinical features of these syndromes. Monosodium urate crystals stimulate IL-1β secretion via cryopyrin, which led to the addition of gout to the spectrum of autoinflammatory diseases.Summary-Advances in our understanding of the autoinflammatory diseases have led to renewed interest in the innate immune system, and its role in the pathogenesis of more common rheumatic diseases.

M‐CSF induces the expression of a membrane‐bound form of IL‐18 in a subset of human monocytes differentiating in vitro toward macrophages

“…IL-1β is the most-studied member and, although measurable levels in supernatants as well as serum are low and, in disease, rarely correlate with severity, it is involved in the pathogenesis of different autoinflammatory diseases. IL-1β neutralization by IL-1Ra, a natural-occurring IL-1β antagonist known as anakinra or by anti-IL-1β mAbs successfully entered the clinical practice and in some cases was life saving [5,30,31]. Monocytes and macrophages do not constitutively express mRNA for pro-IL-1β and IL-1β secretion requires two signals.…”

Pediatric hereditary autoinflammatory syndromes

“…Estudos adicionais sugerem também que o receptor mutado apresenta um tráfego intracelular alterado, com retenção da proteína no interior do retículo endoplasmático. Essa agregação intracelular do receptor poderia ocasionar sua ativação espontânea com desencadeamento de resposta inflamatória 44,45 . Outro mecanismo fisiopatológico é o defeito na apoptose de neutrófilos que ocorre em alguns pacientes com TRAPS, o que também ocasionaria uma perpetuação da resposta inflamatória 45,46 .…”

Síndromes autoinflamatórias hereditárias na faixa etária pediátrica

“…This intracellular buildup of the receptor could lead to spontaneous activation, triggering an inflammatory response. 44,45 Another pathophysiological mechanism is a defect in neutrophil apoptosis that occurs in some patients with TRAPS and is believed to possibly perpetuate the inflammatory response. 45,46 The clinical manifestations of TRAPS usually arise in childhood or adolescence (mean age, 10 years; range, 1 to 63 years).…”

“…44,45 Another pathophysiological mechanism is a defect in neutrophil apoptosis that occurs in some patients with TRAPS and is believed to possibly perpetuate the inflammatory response. 45,46 The clinical manifestations of TRAPS usually arise in childhood or adolescence (mean age, 10 years; range, 1 to 63 years). 6,7 Duration of fever is longer than in any other AIS: 14 days on average, ranging from 2 to 56 days.…”